Viral hepatitis is still a public health problem affecting several million people around the world.Neutrophils are polymorphonuclear cells that have a critical role in antibacterial infection.However,the role of neutr...Viral hepatitis is still a public health problem affecting several million people around the world.Neutrophils are polymorphonuclear cells that have a critical role in antibacterial infection.However,the role of neutrophils in viral infection is not fully understood.By using a mouse model of lymphocytic choriomeningitis virus infection-induced viral hepatitis,we observed increased neutrophil recruitment in the liver accompanied by enhanced CD8+T-cell responses.Liver neutrophils expressed high levels of immunomodulatory cytokines,such as C-X-C chemokine ligand 2,arginase-1,inducible nitric oxide synthase and interleukin(IL)-10,demonstrating immunosuppressive properties.Depletion of neutrophils in vivo by a neutralizing antibody resulted in the exacerbation of liver injury and the promotion of T-cell responses at the immune contraction stage.IL-33 significantly induced neutrophil recruitment in the liver and attenuated liver injury by limiting effector T-cell accumulation.Mechanistically,we found that IL-33 promoted the expression of arginase-1 in neutrophils through the type 2 innate lymphoid cell(ILC2)-derived IL-13.Additionally,IL-13 increased the inhibitory effect of neutrophils on CD8+T-cell proliferation in vitro,partially through arginase-1.Finally,we found that IL-13 induced arginase-1 expression,depending on signal transducer and activator of transcription factor 6(STAT6)signaling.Therefore,IL-33 induced immunosuppressive neutrophils via an ILC2/IL-13/STAT6 axis.Collectively,our findings shed new light on the mechanisms associated with IL-33-triggered neutrophils in the liver and suggest potential targets for therapeutic investigation in viral hepatitis.展开更多
Type 1 interferon （IFN-I） promotes antigen-presenting cell maturation and was recently shown to induce hepatic IL-7 production during infection. Herein, we further explored the underlying mechanisms used by I FN-I t...Type 1 interferon （IFN-I） promotes antigen-presenting cell maturation and was recently shown to induce hepatic IL-7 production during infection. Herein, we further explored the underlying mechanisms used by I FN-I to orchestrate antiviral immune responses in the liver. Acute viral hepatitis was induced by i.v. injection of adenovirus （Ad） in IFN-a receptor knockout （IFNAR-/-） and control mice. To disrupt signaling, monoclonal antibodies （mAbs） against IL-7 receptor alpha （IL-7Re） or PD-L1 were i.p. injected. We found that CD8＋ T cells in IFNAR-/- mice were less effective than those in control mice. The reduced T-cell function was accompanied by increased levels of PD-1 expression, apoptosis and decreased IFN-7 production. The lack of IFN-I signaling also impaired the expression of accessory molecules in both intrahepatic dendritic cell （DCs） and hepatocytes. PD-L1 was comparably and highly expressed on hepatocytes in both IFNAR-/- and control mice. Injection of PD-Ll-specific mAb in IFNAR-/- mice reversed the compromised immune responses in the liver. Further investigation showed that hepatic IL-7 elevation was less pronounced in IFNAR-/- mice compared to the controls. A treatment with recombinant IL-7 suppressed PD-1 expression on CD8＋ T cells in vitro. Accordingly, blocking IL-7R signaling in vivo resulted in increased PD-1 expression on CD8＋ T cells in Ad-infected mice. Collectively, the results suggest that IFN-I-induced hepatic IL-7 production maintains antiviral CD8＋ T-cell responses and homeostasis by suppressing PD-1 expression in acute viral hepatitis.展开更多
基金in part,by grants from the NIH(AI109100 and AI126371 to JS)PY was a visiting scientist partially supported by the Department of Infectious Diseases,Xiangya Hospital,China and the Natural Science Foundation of Hunan Province(no.14JJ6003)DMKY and ZK were recipients of summer internships from an NIAID T35 training grant(AI078878,PI:LS).
文摘Viral hepatitis is still a public health problem affecting several million people around the world.Neutrophils are polymorphonuclear cells that have a critical role in antibacterial infection.However,the role of neutrophils in viral infection is not fully understood.By using a mouse model of lymphocytic choriomeningitis virus infection-induced viral hepatitis,we observed increased neutrophil recruitment in the liver accompanied by enhanced CD8+T-cell responses.Liver neutrophils expressed high levels of immunomodulatory cytokines,such as C-X-C chemokine ligand 2,arginase-1,inducible nitric oxide synthase and interleukin(IL)-10,demonstrating immunosuppressive properties.Depletion of neutrophils in vivo by a neutralizing antibody resulted in the exacerbation of liver injury and the promotion of T-cell responses at the immune contraction stage.IL-33 significantly induced neutrophil recruitment in the liver and attenuated liver injury by limiting effector T-cell accumulation.Mechanistically,we found that IL-33 promoted the expression of arginase-1 in neutrophils through the type 2 innate lymphoid cell(ILC2)-derived IL-13.Additionally,IL-13 increased the inhibitory effect of neutrophils on CD8+T-cell proliferation in vitro,partially through arginase-1.Finally,we found that IL-13 induced arginase-1 expression,depending on signal transducer and activator of transcription factor 6(STAT6)signaling.Therefore,IL-33 induced immunosuppressive neutrophils via an ILC2/IL-13/STAT6 axis.Collectively,our findings shed new light on the mechanisms associated with IL-33-triggered neutrophils in the liver and suggest potential targets for therapeutic investigation in viral hepatitis.
文摘Type 1 interferon （IFN-I） promotes antigen-presenting cell maturation and was recently shown to induce hepatic IL-7 production during infection. Herein, we further explored the underlying mechanisms used by I FN-I to orchestrate antiviral immune responses in the liver. Acute viral hepatitis was induced by i.v. injection of adenovirus （Ad） in IFN-a receptor knockout （IFNAR-/-） and control mice. To disrupt signaling, monoclonal antibodies （mAbs） against IL-7 receptor alpha （IL-7Re） or PD-L1 were i.p. injected. We found that CD8＋ T cells in IFNAR-/- mice were less effective than those in control mice. The reduced T-cell function was accompanied by increased levels of PD-1 expression, apoptosis and decreased IFN-7 production. The lack of IFN-I signaling also impaired the expression of accessory molecules in both intrahepatic dendritic cell （DCs） and hepatocytes. PD-L1 was comparably and highly expressed on hepatocytes in both IFNAR-/- and control mice. Injection of PD-Ll-specific mAb in IFNAR-/- mice reversed the compromised immune responses in the liver. Further investigation showed that hepatic IL-7 elevation was less pronounced in IFNAR-/- mice compared to the controls. A treatment with recombinant IL-7 suppressed PD-1 expression on CD8＋ T cells in vitro. Accordingly, blocking IL-7R signaling in vivo resulted in increased PD-1 expression on CD8＋ T cells in Ad-infected mice. Collectively, the results suggest that IFN-I-induced hepatic IL-7 production maintains antiviral CD8＋ T-cell responses and homeostasis by suppressing PD-1 expression in acute viral hepatitis.
